Tumor Immunology Flashcards
How does anti-tumor immune response differ against syngeneic vs allogeneic tumors?
Syngeneic - no response (seldom rejected)
Allogeneic - often rejected, due to different MHC haplotype
What are the three phases of immunosurveillance?
- Elimination phase - immune system finds and destroys potential cancers
- Equilibrium - elimination is not completely successful and tumors immunoedit
- Escape phase - tumors start growing unimpeded after sufficiency mutations
What are the “distress signals” associated with tumor cells? What recognizes them?
DAMPs - damage associated molecular patterns
- include HSP, HIF (hypoxia-inducible factor), KAR ligands,
- Recognized by macrophages, dendritic cells (TLRS) and NK cells
What type of antibodies are found in the patient’s serum during the escape phase and what does this indicate?
IgM more prevalent -> lack of T cell help
Tumor-infiltrating lymphocytes will become unresponsive
Give two tumor types common in immunosuppressed patients
- Kaposi’s sarcoma - HHV8
- Burkitt’s lymphoma- EBV (HHV4)
Herpes and epstein barr
What are the two types of receptors on NK cells?
- KIR (i.e. NKG2A)- killer inhibitory receptors - bind MHC Class 1 to prevent NK cytotoxicity
- KAR (i.e. NKG2D) - killer activating receptors - bind MIC-A or MIC-B on tumor and activate lysis
What are MIC-A and MIC-B?
Glycoproteins related to MHC Class 1 which can activate NK cells via NKG2D receptor when they are expressed
Do NK’s have TLRs?
Yes, they can also be induced by TLR3 and TLR1 - activated by DAMPs
Why does downregulation of MHC Class 1 target cells for NK destruction?
Loss of KIR signal, swinging favor of KAR-induced cell death
When do cancers express KAR ligands?
During neoplastic stress, making them susceptible to lysis by NK cells
What two cytokines are antitumor and why?
IFN-y -increase inflammation and immune response
IL-12 - third signal needed for T cell activation
What four cytokines are pro-tumor?
- TGF-beta - immune suppression
- IL-10 -immune suppression
- IL-6 - inflammatory, but important tumor growth factor
- VEGF - for angiogenesis
What two cytokines are contextual in their effect?
- IL-2 - could also stimulate Treg population
2. TNF-alpha - could also activate tumor cells
What cell type is needed for the elimination but no equilibrium phase?
NK cells -> do not play a significant role in inhibiting tumor growth during equilibrium phase
What are some changes in tumor cells that can mediate immune escape?
- Antigen loss variant - loss of antigen not needed for growth / proliferation
- Reduction of MHC 1 expression
- Modulation of apoptosis genes - resistance to Fas and caspase-mediated apoptosis
What are the two macrophage phenotypes, and which one is pro tumor?
M1 = cytotoxic macrophage M2 = suppressive, woundhealing macrophage which is pro-tumor
How can tumors modify the immune response in their favor?
Polarization of immunity towards pro-tumor phenotype:
Induce Treg cells, M2 cells
Induce anergy via lack of co-stimulation
Secrete suppressive cytokines TGFbeta and IL-10
What is an MDSC? What surface marker do they express?
Myeloid-derived suppressor cell which can be induced by tumors to downregulate T cell response using TGFb and PDL1
Express CD11b, and CD15+ is a granulocyte
How might a tumor cell physically evade an immune response?
Growth in a nodule so areas are not accessible to T cells
What other MHC Class 1 types can tumors express for escape?
- HLA-E - binds KIR on NK cells
2. HLA-G - silences NK cells, suppresses T cells and monocytes. Same marker express by fetal cells to avoid maternal MHC
Why is downregulation of TAP good for tumor cells?
Reduced MHC 1 expression or MHC loaded with low affinity peptides
-> avoid CD8+ T cell killing and NK cell killing
Why can mast cells be important for tumor growth?
Activated during inflammation, they release proteases which initiate angiogenesis
What cytokines do tumor associated macrophages release to promote tumor growth?
Suppression: IL-10, TGF-beta, PDL1, arginase 1
MMPs for metastasis
VEGF for angiogenesis
How do MDSCs activate Treg cells?
CD40-CD40L interaction to induce tolerance to tumor cell expressed antigen
How do monocytic MDSCs differ from granulocytic?
Monocytic - use NO and cytokines
Granulocytes - use ROS (think of granules wanting to use reactive oxygen species)
What is IL-10 normally used for, and what is its use in cancer?
IL-10 normally prolongs B cell life and antibody production
In cancer, it regulates MHC downregulation, tumor growth, metastasis, and EMT
How can we stop tumor PDL1 expression?
Give antibodies to PDL1, to prevent use of PDL1 for apoptosis of immune cells
What is the function of CD47?
Blocks phagocytosis by dendritic cell
Why is Tim-3 a good antigen target? What is it functionally analogous to?
Expressed primarily in intratumoral cells
Analogous to PD1 / CTLA4
Why are nonspecific approaches to cancer immune therapy not very good?
Use cytokines such as IL-2 which can also stimulate T-reg cells
How does the dendritic cell based cancer vaccine work?
Activates both the cellular and humoral immune responses
Must sensitize and culture DCs in the presence of the resected tumor, and vaccinate the patient with these, while also expanded the T cell population ex vivo (combined therapy)
What type of treatment is monoclonal antibodies for cancer considered?
An adoptive humoral treatment
What is an adoptive cellular cancer treatment?
Infusion of ex vivo expanded tumor-reactive T cells
What is a LAK cell?
Lymphokine active killer cell
What is a TRA?
Tumor rejection antigen - an antigen specific for tumors of a specific type which can be used as a vaccine target
What is antibody-dependent cell-mediated cytotoxicity (ADCC)?
Monoclonal antibodies can recruit NK cells to cause tumor cell lysis
What is ADEPT?
Antibody-directed enzyme / prodrug therapy
-bring prodrug to tumor then activate with exnzyme
What is immunodiagnostics?
Field of study by which monoclonal antibodies and tests can be used to determine tumor progression via various markers
What is Gardasil prophylactic for?
HPV 16 and 18 causing cervical cancer
HPV 6 and 11 - causing genital warts
